1. Field of Invention
This invention relates to compounds and methods for the prevention and/or treatment of infection after stroke or central nervous system (CNS) injury.
2. Description of Related Art
The invention discloses agents for the prevention of infections after ischemic stroke or other CNS injury in order to reduce lethality and morbidity. Infections are severe complications, which commonly occur in the early phase after stroke and have a negative prognostic influence. The agents employed according to the invention, in pharmaceutical preparations, constitute substances which are glucocorticoid receptor antagonists. The invention moreover refers to agents for therapy after stroke, this approach having the aim to prevent and/or treat infections after stroke.
The stroke patient, besides the direct consequences of stroke, which may range from transitory to permanent neurological failures or death in the acute and early remission phase, is particularly endangered by infections. Infections, especially pneumonias, constitute the major cause of lethality in stroke (Henon et al. 1995, Katzan et al. 2003, List of References following the examples). Thus, 21-65% of acute stroke patients develop infections and 10-22% develop pneumonias (Davenport et al. 1996, Castillo et al. 1998, Johnston et al. 1998, Grau et al. 1999, Georgilis et al. 1999, Langhorne et al. 2000). The comparison with the incidence of nosocomial infections occurring in an average of 7-10% of all patients (Bucher 2000) and about 3% of postoperative patients (Smyth & Emmerson 2000), particularly underlines the very high frequency of infections in acute stroke patients. In a systematic investigation, it was shown, that the risk of infection is highest at the first and second day after stroke (Grau et al. 1999). See FIG. 1.
There is increasing evidence that normally well balanced brain-immune interactions become dysregulated after stroke. CNS injury, such as stroke, induces immunodepression thought to be mediated largely by elevated circulating cortisol, either as a stress response or related primarily to the neural pathways impaired by the stroke itself. Elevated concentrations of cortisol in patients with acute stroke are associated with more severe stroke, larger infarct volume and worse outcome. Thus, there is a need for methods for the prevention and/or treatment of infection after stroke. The prevention of stroke-induced infections by means of, for example, a glucocorticoid receptor antagonist as a means of a preventive, anti-infective therapy constitutes a novel approach. The present invention relates to the blocking of this early rise of cortisol by the administration of such a glucocorticoid receptor antagonist. It is expected that a short treatment with a glucocorticoid receptor antagonist after stroke will diminish or prevent the occurrence of infections and will also have a positive impact on infarct severity and long term outcome.
All references cited herein are incorporated herein by reference in their entireties.